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Eerdman/sandbox
Clinical data
Routes of
administration		oral, i.v.
ATC code
  • none
Identifiers
  • cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
Chemical and physical data
FormulaC16H18N2O2
Molar mass270.33 g·mol−1
3D model (JSmol)
  • C1CC1C(=O)C2=CC=C(C=C2)OCCCC3=CN=CN3
  • InChI=1S/C16H18N2O2/c19-16(12-3-4-12)13-5-7-15(8-6-13)20-9-1-2-14-10-17-11-18-14/h5-8,10-12H,1-4,9H2,(H,17,18)
  • Key:ACQBHJXEAYTHCY-UHFFFAOYSA-N
 ☒NcheckY (what is this?)  (verify)

Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.

The histamine H3 receptor is a Gi/o-coupled inhibitory autoreceptor primarily located on histaminergic nerve terminals, and is involved in modulating the release of histamine and other aminergic/peptidergic neurotransmitters in the brain.[1][2] Drugs such as ciproxifan, which block the H3 receptor, lead to increased release of histamine and other excitatory neurotransmitters in the prefrontal cortex, hippocampus, and entorhinal cortex. [3] [4] The histaminergic system has been shown to be involved in wakefulness, cognition, food intake, and seizures. [5] [6] [7] [8]

Synthesis

[edit]

There are multiple synthesis paths for Ciproxifan. One produces the compound through Mitsunobu reaction of imidazolyl trityl-protected 3-(1H-imidazol-4-yl)propanol prepared in four steps from urocanic acid with cyclopropyl 4-hydroxy-phenyl methanone and following acidic deprotection. A simpler synthesis with a lower cost and work expenditure synthesizes Ciproxifan through a nucleophilic exchange reaction between trityl-protected 3-(1H-imidazol-4-yl)propanolate and 4-chloro-4'-fluorobutyrophenone in an excess of sodium hydride, which creates an intermediate that is then worked up by extraction, detritylation, and additional extraction to obtain the final desired product. [9]

Pharmacokinetics

[edit]

Ciproxifan is a member of a series of potent H3-receptor antagonists, many of which have a high capacity for oral absorption and brain penetration. [10] [11] Thioperamide, another member of this series, was identified as a potential drug for treating psychiatric disorders. However, due to its low bioavailability and liver toxicity, effort was put into finding other safer drugs with higher potency. [11] Ciproxifan appears to be a better option, with an oral bioavailability of 62% and ability to cross the blood brain barrier due to its neutral charge, making oral administration a viable option.[11] [12] Maximal dose of Ciproxifan ranges from 3-10 mg/kg, and can be administered orally, intraperitoneally, or intravenously. [13] [11][14]

Pharmacodynamics

[edit]

Ciproxifan is a competitive antagonist/inverse agonist that is highly selective for the H3 receptor. It has an IC50 of 9.2 nM and a Ki value of 1.0 ± 0.3 nM. It has a higher affinity than many related H3 antagonists such as Thioperamide, which has a Ki of about 4 nm, and Carbonperamide, which has a Ki of about 20nm. Ciproxifan acts at the synapse by preventing the autoreceptor H3 from modulating histamine synthesis/release. While it does not directly increase histamine release, the lack of H3 modulation leads to an increased histamine level. [11]

Treatment

[edit]

Because of the wide influence of the histaminergic system, Ciproxifan has been studied as a treatment for a variety of diseases and conditions, such as obesity, pain, sleep disorders, schizophrenia, attention deficit hyperactivity disorder, Alzheimer's, and cognitive degeneration associated with aging. [13][15]

Schizophrenia

[edit]

H3 receptors have connections to the dopaminergic system, for example, showing co-expression with D1 and D2 receptors. [14] Ciproxifan potentiates the effects of antipsychotics, although it does not have antipsychotic properties itself. [2] [14] It has been suggested as an adjunctive medication for schizophrenia, as the positive effects it has on attention and memory may help to treat the cognitive symptoms of schizophrenia. [14]

Sleep Disorders

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H1 receptors are known to be involved in sleep/wakefulness states. These receptors are activated by endogenous histamine, which is increased by Ciproxifan. In cats, Ciproxifan has been shown to increase wakefulness by suppressing neocortical slow activity and spindles and increasing neocortical fast rhythms. [11] Increased wakefulness could be helpful in the treatment of narcolepsy or enhancing vigilance in old age.[15]

Alzheimer's Disease

[edit]

While Ciproxifan is not yet in clinical trials, it may be helpful in the treatment of Alzheimer's Disease. In the amyloid precursor protein transgenic mouse model of Alzheimer's disease, Ciproxifan was shown to improve spatial memory, novel object recognition, and decrease hyperactivity. [13] Since H3 densities do not degenerate through the disease progression, Ciproxifan could prove a valuable treatment throughout the progression of the disease. [13]

Cognitive Enhancement

[edit]

Because of the importance of the histaminergic system on wakefulness and cognition, Ciproxifan has been looked into for enhancing cognition. In rats, Ciproxifan has been found to increase attentiveness in a serial reaction-time task when a duration of 0.25 seconds was used. [11] Short term memory may also be a target, as Ciproxifan was shown to enhance short term memory in an adult rat social recognition model.[16]

Obesity

[edit]

While it has not been studied extensively in relation to obesity, Ciproxifan has shown some promise in treating obesity. In a mouse model of diet induced obesity, it was shown to decrease weight gain. [17]

Potential Side Effects

[edit]

Ciproxifan has not been used in clinical trials, so there are not established side effects in humans. However, as the H3 receptor is also present in the peripheral nervous system, including the gastrointestinal tract, the airways, and the cardiovascular system, it may have unintended effects if it becomes a clinically viable drug. Looking specifically at H3 antagonists, possible adverse side effects could include increased locomotor activity[18] and pituitary hormone secretion[19], and suppressed food intake. [20]

References

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  1. ^ Schlicker, E (1994). "Modulation of neurotransmitter release via histamine H3 heteroreceptors". Fundamental & Clinical Pharmacology. 8 (2): 128–37. doi:10.1111/j.1472-8206.1994.tb00789.x. PMID 8020871. S2CID 21816655. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ a b Pillot, C (2002 Aug 15). "Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 22 (16): 7272–80. doi:10.1523/JNEUROSCI.22-16-07272.2002. PMC 6757889. PMID 12177222. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  3. ^ Clapham, J (1992 Dec). "Histamine H3 receptors modulate the release of [3H]-acetylcholine from slices of rat entorhinal cortex: evidence for the possible existence of H3 receptor subtypes". British Journal of Pharmacology. 107 (4): 919–23. doi:10.1111/j.1476-5381.1992.tb13386.x. PMC 1907926. PMID 1334753. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ Medhurst, AD (2007 Jun). "GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models". The Journal of Pharmacology and Experimental Therapeutics. 321 (3): 1032–45. doi:10.1124/jpet.107.120311. PMID 17327487. S2CID 14312511. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ Lin, JS (2000 Oct). "Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons". Sleep Medicine Reviews. 4 (5): 471–503. doi:10.1053/smrv.2000.0116. PMID 17210278. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Hancock, AA (2004 Oct). "Perspectives on cognitive domains, H3 receptor ligands and neurological disease". Expert Opinion on Investigational Drugs. 13 (10): 1237–48. doi:10.1517/13543784.13.10.1237. PMID 15461554. S2CID 9847606. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Hancock, AA (2003 Oct). "H3 receptor antagonists/inverse agonists as anti-obesity agents". Current Opinion in Investigational Drugs (London, England : 2000). 4 (10): 1190–7. PMID 14649210. {{cite journal}}: Check date values in: |date= (help)
  8. ^ Kamei, C (2001 Oct 15). "Involvement of central histamine in amygdaloid kindled seizures in rats". Behavioural Brain Research. 124 (2): 243–50. doi:10.1016/s0166-4328(01)00218-2. PMID 11640977. S2CID 27089892. {{cite journal}}: Check date values in: |date= (help)
  9. ^ Stark, H (2000 Sep). "Convenient procedures for synthesis of ciproxifan, a histamine H3-receptor antagonist". Archiv der Pharmazie. 333 (9): 315–6. doi:10.1002/1521-4184(20009)333:9<315::AID-ARDP315>3.0.CO;2-M. PMID 11039189. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Stark, H (1996 Mar 1). "Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity". Journal of Medicinal Chemistry. 39 (5): 1157–63. doi:10.1021/jm9507688. PMID 8676353. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ a b c d e f g Ligneau, X (1998 Nov). "Neurochemical and behavioral effects of ciproxifan, a potent histamine H3-receptor antagonist". The Journal of Pharmacology and Experimental Therapeutics. 287 (2): 658–66. PMID 9808693. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ "ciproxifan - Compound Summary". PubChem.
  13. ^ a b c d Bardgett, ME (2011 Jan). "Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APP Tg2576 mouse model of Alzheimer's disease". Neurobiology of Learning and Memory. 95 (1): 64–72. doi:10.1016/j.nlm.2010.10.008. PMC 3034295. PMID 21073971. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ a b c d Burban, A (2010 Jul). "Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists". Psychopharmacology. 210 (4): 591–604. doi:10.1007/s00213-010-1863-2. PMID 20437030. S2CID 1893960. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  15. ^ a b Witkin, JM (2004 Jul). "Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system". Pharmacology & Therapeutics. 103 (1): 1–20. doi:10.1016/j.pharmthera.2004.05.001. PMID 15251226. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ Buccafusco, ed. by Jerry J. (2004). Cognitive enhancing drugs. Basel [u.a.]: Birkhäuser. p. 105. ISBN 3-7643-6982-5. {{cite book}}: |first= has generic name (help)
  17. ^ Vohora, editor, Divya (2009). The third histamine receptor : selective ligands as potential therapeutic agents in CNS disorders. Boca Raton: CRC Press. ISBN 978-1420053920. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link)
  18. ^ Schwartz, JC (1991 Jan). "Histaminergic transmission in the mammalian brain". Physiological Reviews. 71 (1): 1–51. doi:10.1152/physrev.1991.71.1.1. PMID 1846044. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  19. ^ Søe-Jensen, P (1993 Mar). "Responses of anterior pituitary hormones and hypothalamic histamine to blockade of histamine synthesis and to selective activation or inactivation of presynaptic histamine H3 receptors in stressed rats". Neuroendocrinology. 57 (3): 532–40. doi:10.1159/000126402. PMID 8391665. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ Ookuma, K (1993 Nov 19). "Neuronal histamine in the hypothalamus suppresses food intake in rats". Brain Research. 628 (1–2): 235–42. doi:10.1016/0006-8993(93)90960-u. PMID 8313152. S2CID 25117110. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)


Category:Nootropics Category:H3 receptor antagonists Category:Imidazoles Category:Phenol ethers Category:Aromatic ketones Category:Cyclopropanes


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